Ivy and Oddberg [Amer. J. Physiol. 86, 599 (1928)] in 1928 isolated from the mucous membrane of intestines a substance which caused the contraction of the gall-bladder and which they called "cholecystokinin". Harper and Raper [J. Physiol. 102, 115 (1943)] later described a substance called by these authors "pancreozymin", which was isolated from extracts of intestinal mucous membranes and which increased the enzyme secretion of the pancreas. Mutt and Jorpes [Acta Chem. Scand. 18, 2408 (1964)] have shown that both biological effects are caused by the same substance, a hormone called by these authors "cholecystokinin-pancreozymin". The same authors have also determined the amino acid sequence of this hormone [Biochem. J. 125, 678 (1971)]: Lys--Ala--Pro--Ser--Gly--Arg--Val--Ser--Met--Ile--Lys--Asn--Leu--Gln--Ser- -Leu--Asp--Pro--Ser--His--Arg--Ile--Ser--Asp--Arg--Asp--Tyr(SO.sub.3 H)--Met--Gly--Trp--Met--Asp--Phe--NH.sub.2. Ondetti and Pluscec [J. Am. Chem. Soc. 92, 195 (1970); J. Med. Chem. 13, 349 (1970)] synthesized the sulfate ester of C-terminal octapeptide amide of cholecystokinin-pancreozymin, hereinafter CCK(1-8), and a series of analogous compounds, and found that the octapeptide amide sulfate ester as well as some analogous compounds have a considerably higher activity than the complete molecule of cholecystokinin-pancreozymin.
This sulfate ester octapeptide amide, when administered in doses of about 1.0-6.0 .mu.g/kg. of body weight, is a useful diagnostic means for the examination of the contraction of the gall bladder and to control pancreatic secretion. When administered i.v. at low dosages, the peptide exhibits some gastrinic activity in causing secretion of gastric acid. More recent investigations have also revealed that the octapeptide amide sulfate ester exerts a strong relaxing action on the muscle sphincter Oddii; thus, this compound can be used with good results to alleviate the spasms occurring after gall-bladder operations [see M. A. Ondetti, B. Rubin, S. Engel: J. Amer. Digestive Diseases 15, 149 (1970)]. CCK has also been found to serve as a brain neurotransmitter and to regulate appetite and have other effects upon the central nervous system, as described in detail in a review by Morley, J. E., Life Sciences, 30, 479-493 (1982).
Investigators have sought analogs of these octapeptides having improved therapeutic properties.